This proposal request support for the 8th Gordon Research Conference on 3-Dimensional Electron Microscopy of Macromolecules. Electron microscopy occupies a unique position in the biological armamentarium in that it can address questions at the molecular level that can not be approached using other structural methods. In recent years, important technical breakthroughs have been made that enable 3-D structures to be determined with ever increasing accuracy, and which have opened the way to the study of macromolecular systems under defined physiological conditions. As a result, there are exciting new opportunities for understanding biological mechanisms, interactions between macromolecules and the principles of biomolecular design. This series of conferences fosters an integrated view of biological complexity by bringing together scientists working at different levels of structural hierarchy. These meetings serve to define the challenges of the future and to focus a concerted approach to problems in the preparation, imaging and interpretation of biological specimens that range in size from the molecular to the subcellular. The impact of the preceding seven conferences has been such that the 3-D EM community has come to regard this Gordon Conference as an event of pivotal importance. The theme of the conference is "New Challenges for Three Dimensional Electron Microscopy". In organizing this conference, our goal has been to create a dynamic forum for the dissemination of the major progress in the field over the past two years, and identification of the new technical and biological challenges that the field must address in order for 3-D EM to become an essential and ubiquitous tool for the solution of cell biological problems. In the spirit of the Gordon Conference, the applicants have chosen a program that represents the frontier of the field. Speakers have been chosen on the basis of the importance of their recent contributions and the potential impact of their particular research approach in future work in this field. Based on past experience, the applicants confidently expect that the 3-D EM Gordon Conference will continue to play a central role in defining new technical challenges, and in focusing a concerted approach to the understanding of fundamental biological questions.